Essential Role of TGF-beta Signaling in Glucose-Induced Cell Hypertrophy

Dev Cell. 2009 Jul;17(1):35-48. doi: 10.1016/j.devcel.2009.05.010.

Abstract

In multicellular organisms, cell size is tightly controlled by nutrients and growth factors. Increasing ambient glucose induces enhanced protein synthesis and cell size. Continued exposure of cells to high glucose in vivo, as apparent under pathological conditions, results in cell hypertrophy and tissue damage. We demonstrate that activation of TGF-beta signaling has a central role in glucose-induced cell hypertrophy in fibroblasts and epithelial cells. Blocking the kinase activity of the TbetaRI receptor or loss of its expression prevented the effects of high glucose on protein synthesis and cell size. Exposure of cells to high glucose induced a rapid increase in cell surface levels of the TbetaRI and TbetaRII receptors and a rapid activation of TGF-beta ligand by matrix metalloproteinases, including MMP-2 and MMP-9. The consequent autocrine TGF-beta signaling in response to glucose led to Akt-TOR pathway activation. Accordingly, preventing MMP-2/MMP-9 or TGF-beta-induced TOR activation inhibited high glucose-induced cell hypertrophy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Cell Line
  • Cell Size
  • Diabetes Mellitus / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Fibroblasts / cytology
  • Fibroblasts / physiology
  • Glucose / metabolism*
  • Hyperglycemia / metabolism*
  • Hyperglycemia / physiopathology
  • Hypertrophy / metabolism*
  • Hypertrophy / physiopathology
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Mice, Knockout
  • Neoplasms / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Rats
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / physiology*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism
  • TOR Serine-Threonine Kinases
  • Transforming Growth Factor beta / metabolism*

Substances

  • Receptors, Transforming Growth Factor beta
  • Smad3 Protein
  • Transforming Growth Factor beta
  • Protein Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Tgfbr1 protein, rat
  • Matrix Metalloproteinase 2
  • Matrix Metalloproteinase 9
  • Glucose